METTL3 promotes gastric cancer progression via modulation of FNTA-mediated KRAS/ERK signaling activation.

As a vital form of post-transcriptional modification, RNA N6-methyladenosine methylation (m6A) dysregulation is usually associated with the pathogenesis of a range of diseases, including cancer, but the function and underlying mechanisms of m6A in regulating gastric cancer initiation and progression are still poorly understood. Here, we have found methytransferase like 3 (METTL3) and the level of RNA m6A modification were significantly upregulated in gastric cancerous tissues relative to their normal counterparts. In addition, higher METTL3 expression always predicted poorer outcomes for patients with gastric cancer. Methylated RNA sequencing revealed that METTL3 deposited m6A modification on FNTA (farnesyltransferase, subunit alpha) mRNA and accelerated its translation relying on YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) recognition. When METTL3 or FNTA expression was silenced in gastric cancer cells, the FNTA-mediated KRAS plasma membrane distribution was disrupted, resulting in downstream MEK/ERK signaling inactivation, which finally contributed to gastric cancer suppression in vitro and in vivo. In summary, our studies revealed a crosstalk between METTL3-mediated RNA methylation and FNTA-mediated protein modification which synergized to drive gastric cancer progression through orchestrating KRAS/ERK signaling activity. Implications: Targeting METTL3/FNTA pathway will provide an alternative to overcome the resistance of gastric cancer to canonical KRAS inhibitors.